Hypothermal inhalation gas composition

ABSTRACT

The present invention relates to an inhalation gas composition including oxygen and a mixture of inert gases, characterized in that said mixture of inert gases comprises a first compound selected from xenon and argon having hyperthermal properties, and a second compound having hypothermal properties, said mixture of inert gases comprising proportions of the first compound and of the second compound such that said mixture of inert gases is hypothermal.

The present invention relates to an inhalation gas composition and moreparticularly to a selection of appropriate proportions of the gases ofthe composition.

In the case of ischemia followed by a reperfusion, and for example inthe case of CVA (acronym for “cerebrovascular accident”), neonatalencephalopathy, or therapeutic ischemia such as ischemia due to an organtransplantation or to the placement of a clamp during a surgicalintervention, in particular in cardiac surgery, it is conventional toset up a controlled hypothermia for the purpose of protecting the brainby reducing the cell metabolism.

Such a setting up of hypothermal conditions is still very often the onlytherapy proposed in the context of neurological (ischemic ornon-ischemic) and psychiatric pathologies (“Drug Treatment inPsychiatry,” Trevor Silverstone and Paul Turner Eds., 1995 (p. 291)).

Xenon is an anesthetic agent which has had a marketing authorization inEurope since 2007. It is probably as a glutaminergic receptor antagonistof the N-methyl-D-aspartate (NMDA) type and due to its anti-proteolyticeffect that xenon has organoprotective and in particular neuroprotectiveproperties (“Xenon: elemental anaesthesia in clinical practice,” RobertD. Sanders, Daqing Ma and Mervyn Maze, British Medical Bulletin (2005)71 (1): 115-135).

Studies have also shown that argon, a type A GABAergic receptor agonist(“Gamma-aminobutyric acid neuropharmacological investigations onnarcosis produced by nitrogen, argon, or nitrous oxide,” Abraini J H,Kriem B, Balon N, Rostain J C, Risso J J, Anesthesia and Analgesia 2003;96:746-9) and mu type opioidergic receptor antagonist (“Argon blocks theexpression of locomotor sensitization to amphetamine through antagonismat the vesicular monoamine transporter-2 and mu-opioid receptor in thenucleus accumbens,” David H N, Dhilly M, Degoulet M, Poisnel G, MecklerC, Vallée N, Blatteau J É, Risso J J, Lemaire M, Debruyne D, Abraini JH, Translational Psychiatry 2015; 5:e594), has organoprotective and inparticular neuroprotective properties (“Argon: Systematic Review onNeuro- and Organoprotective Properties of an “Inert” Gas,” A. Höllig, A.Schug, A V. Fahlenkamp, R. Rossaint, M. Coburn and ArgonOrgano-Protective Network (AON), International Journal of MolecularSciences, 2014 October; 15(10): 18175-18196)).

However, xenon and argon have the disadvantage of having hyperthermalproperties for certain inhalation temperatures, these inert gases havinga higher molecular weight than that of nitrogen and a lower thermalconductivity than that of nitrogen, which gives them a hyperthermalcharacter when they are used in inhalation gas compositions. Now the useof a gas with hyperthermal properties will tend to put the subjects whoinhale it in a state of hyperthermia, which is detrimental in thecontext of the therapies of most neurological or psychiatric diseases.

It results from this that the use of xenon or argon would require aparallel cooling of the subject inhaling these inert gases, inparticular by independent mechanical cooling means, in order to reach ageneral state of hypothermia.

These independent cooling means such as bags of water or cold gel areapplied directly on the body or the area to be cooled. The independentcooling means can also consist of the use of a hydraulic pad withadjustable temperature or of selective cooling carried out with the aidof a refrigerated water circuit. However, such cooling means by directapplication on the skin do not make it possible to achieve an optimalcooling of the subject, that is to say a homogeneous cooling, it beingunderstood that a temperature gradient forms between the skin in contactwith the cooling means and the internal organs.

In this context, the subject matter of the invention is thus aninhalation gas composition including oxygen and a mixture of inertgases. The mixture of inert gases includes a first compound selectedfrom xenon and argon having hyperthermal properties, and a secondcompound having hypothermal properties, said mixture of inert gasescomprising proportions of the first compound and of the second compoundsuch that said mixture of inert gases is hypothermal under predeterminedtemperature conditions.

“Inhalation” gas composition is understood to mean a gas compositionincluding at least 21% oxygen, so that it can be inhaled by a subject,it being understood that with less than 21% oxygen in the inhalationmixture, the subject is in a state of hypoxia.

Echoing what was defined above, it is understood that a gas or a mixtureof inert gases having hypothermal properties is defined as being a gasor a mixture having a lower molecular weight than that of nitrogen and ahigher thermal conductivity than that of nitrogen, which thus gives itthe possibility of putting the subject inhaling said gas or mixture in astate of hypothermia. In other words, the gas composition inhaled at acertain temperature makes it possible to maintain the body temperatureof the subjects inhaling it within a so-called hypothermal temperaturerange below 36° C. and more precisely from 32° C. to 35° C.

It is understood that the inhalation of such a composition forinhalation temperatures between 16° C. and 27° C. makes it possible tomaintain a hypothermia of the body, that is to say to maintain a bodytemperature in a hypothermal range, that is to say a range oftemperatures below the range of normal variability of the body, roughlybetween 36.1° C. and 37.8° C. (Simmers, Louise. Diversified HealthOccupations, 2nd ed. Canada: Delmar, 1988: 150-151), it being possibleto round off this range to 36-38° C. or 37 ±1° C. In general, thetherapeutic hypothermal range extends to below 36° C. and morespecifically between 32° C. and 35° C. In other words, the inventionmakes it possible to provide a gas composition which does not generateor does not risk generating an increase in the body temperature ofsubjects inhaling the composition outside of a range of so-calledhypothermal values extending below 36° C. and more specifically from 32°C. to 35° C.

In addition, this gas composition makes it possible to avoid thetemperature gradient between the skin and the internal organs thatoccurs with the use of mechanical cooling means. In other words, theinhalation gas composition makes it possible to achieve an optimalcooling of the subject, that is to say homogeneous cooling.

According to a feature of the invention, the second compound havinghypothermal properties also has organoprotective properties.Organoprotective properties are understood to mean the protection ofinternal organs such as, for example, the brain, blood vessels andnerves. Thus, in addition to maintaining the body temperature in a rangeof values corresponding to a therapeutic hypothermia of the body, theinhalation gas composition according to the invention makes it possibleto protect the internal organs when it is inhaled by a subject.

More precisely, the second compound can advantageously be helium. Infact, helium has both hypothermal and organoprotective properties(“Heliox and oxygen reduce infarct volume in a rat model of focalischemia,” Pan Y, Zhang H, Van Deripe D R, Cruz-Flores S, Pannerton W M(2007), Experimental Neurology 205:587-90; “The effect of helium-oxygenmixtures on body temperature,” Tapper D, Arensman R, Johnson C, FolkmanJ (1974), Journal of Pediatric Surgery 9:597-603; “Post-ischemic heliumprovides neuroprotection in rats subjected to middle cerebral arteryocclusion-induced ischemia by producing hypothermia,” David N H,Haelewyn B, Chazalviel L, Lecocq M, Degoulet M, Risso J J, Abraini J H(2009), Journal of Cerebral Blood Flow & Metabolism 29:1159-1165;“Modulation by the Noble Gas Helium of Tissue Plasminogen Activator:Effects in a Rat Model of Thromboembolic Stroke,” Haelewyn B, David H N,Blatteau J E, Vallée N, Meckler C, Risso J J, Abraini J H (2016),Critical Care Medecine in press).

The inhalation gas composition includes 50% to 79% of the mixture ofinert gases; these proportions make it possible to ensure that thecomposition can be inhaled and to avoid hypoxia of the subject inhalingthe composition.

According to a first series of features of the invention, taken alone orin combination, in the case of application of a first compound in theform of xenon, one can provide that:

said composition includes at least 13% helium.

said composition includes at most 50% xenon. Limiting the xenon contentto less than 50% makes it possible to avoid an anesthetic effect on thesubject inhaling the composition, while at the same time limiting thecosts of obtaining the composition.

According to an embodiment of the invention, for inhalation temperaturesless than or equal to 22° C., one can provide that said compositionincludes 21% to 25% oxygen, 43% to 48% helium, and 30% to 35% xenon.

More precisely, for an oxygen level of 22%, the composition can include45% to 47% helium and 31% to 33% of xenon, or for an oxygen level of25%, it can include 43% to 45% helium and 30% to 32% xenon, in order toensure a body temperature between 32° C. and 35° C. in humans. As anexample, in order to ensure a body temperature of 34° C., saidcomposition can include roughly 22% oxygen, 43% helium, and 35% xenon.Roughly is understood to mean that a margin of error or uncertainty of1% is acceptable.

According to a second series of features of the invention, taken aloneor in combination, in the case of application of a first compound in theform of argon, one can provide that:

said composition includes at least 11% helium.

said composition includes at most 67% argon.

According to an embodiment of the invention, one can provide that saidcomposition includes 21% to 25% oxygen, 22% to 76% helium, and 2% to 56%argon.

More precisely, when the composition is inhaled at a temperature of 22°C., it can include 22% oxygen, 37% to 68% helium, and 10% to 41% argon,or said composition includes 25% oxygen, 36% to 65% helium, and 10% to39% argon, in order to ensure a body temperature between 33° C. and 35°C. in humans.

Other features, details and advantages of the invention will becomeclearer upon reading the description given below for information inconnection with drawings in which:

FIG. 1 is a graphic representation of the rat body temperature as afunction of the temperature of the inhaled gas which is helium (curveC1) or xenon (curve C2);

FIG. 2 is a graphic representation of the rat body temperature as afunction of the temperature of the inhaled gas which is helium (curveC1) or argon (curve C3);

appended table 1 represents the physical properties of the compounds ofthe present invention;

appended table 2 represents the proportions of xenon and of helium as afunction of the proportion of oxygen, of the temperature of inhalationof the composition and of its effect on the body temperature measured inrats;

appended table 3 represents the proportions of argon and of helium as afunction of the proportion of oxygen, of the temperature of inhalationof the composition and of its effect on the body temperature measured inrats.

The air consists mainly of 21% oxygen, 78% nitrogen, and 1% rare gas. Itis roughly equivalent to say that the reference air consists of 21%oxygen and 79% nitrogen, this oxygen content being the minimum valuethat a gas mixture has to contain to avoid hypoxia in a subject inhalingsuch a gas mixture. The gas composition according to the inventioncomprises oxygen and a mixture of inert gases, the proportion ofnitrogen in the air being replaced by the mixture of inert gases.

This mixture of inert gases consists of a first compound havinghyperthermal properties and of a second compound having hypothermalproperties. The proportions of each compound of the mixture of inertgases are such that they enable the inhaled gas composition to maintainthe body temperature of a subject within a so-called hypothermaltemperature range from 32° C. to 35° C.

The composition contains at least 21% oxygen, in order to avoid anyhypoxia during its inhalation. The composition contains at most 50%oxygen, and preferably between 21% and 30%, and even between 21% and25%. The composition thus contains at least 50% of a mixture of inertgases, and preferably 70% to 79%.

The mixture of inert gases includes a first compound selected from inertgases having hyperthermal properties and a second compound selected frominert gases having hypothermal properties. The inert gases have theadvantage of not being metabolized after they have been inhaled.

The first compound selected from the inert gases with hyperthermalproperties is xenon or argon. In fact, as shown in the appended table 1,xenon and argon have a higher molecular weight than nitrogen and a lowerthermal conductivity than nitrogen, which gives them a hyperthermalcharacter when either of the two replaces nitrogen in a gas mixture.

In addition to having hyperthermal properties, xenon and argon haveorganoprotective properties, that is to say that these compounds enablethe protection of organs, blood vessels and nerves. These compounds arecapable of protecting the brain in particular.

Below, a first embodiment of the invention is described, in which thegas composition includes xenon as first compound, that is to say ascompound having the hyperthermal properties.

Xenon is then mixed with a gas having hypothermal properties inproportions such that the mixture has hypothermal properties. Below, aninert gas which is particular in that it has hypothermal properties,namely helium, is selected to be mixed with xenon. In fact, as appendedtable 1 shows, helium has a lower molecular weight than nitrogen and ahigher thermal conductivity than nitrogen, which gives it a hypothermalcharacter when it replaces nitrogen in a gas mixture. Moreover, heliumalso has organoprotective properties.

In order to offer a gas composition which is hypothermal, that is to saywhich does not change the body temperature of subjects inhaling thecomposition outside of a temperature bracket between 32° C. and 35° C.,the proportions of the first compound and of the second compound of themixture of inert gases have to be precisely calculated. Theseproportions are extrapolated in particular from experimental dataobtained with gases constituting the mixture. These experimental data,obtained in rats whose so-called normal body temperature is close tothat of humans, namely between 35.9° C. and 37.5° C. (Animal care anduse committee, Johns Hopkins University,http://web.jhu.edu/animalcare/procedures/rat.html), made it possible toprepare the graphs of FIGS. 1 and 2.

The graph of FIG. 1, which represents the experimental body temperaturedata Tc collected on rats as a function of the inhalation temperature Tiof a helium-oxygen mixture (curve C1) or of a xenon-oxygen mixture(curve C2), makes it possible to determine the proportions of the gascomposition to be complied with in order to obtain a hypothermal gasmixture, depending on the inhalation temperature. In a more detailedmanner, curves C1 and C2 correspond to regression lines obtained basedon said experimental data Pi, several examples of which have beenplotted in FIG. 1.

The experimental data were obtained as follows: The rats were placed for3 hours in a closed enclosure supplied with a continuous flow of a gasmixture containing 22% oxygen (O₂) and 78% helium, xenon or argon (He,Xe or Ar). This gas mixture was administered at different temperatures.The flow of the gas mixture was 10 mL/min and made it possible tomaintain the carbon dioxide (CO₂) concentration below 0.03% and thehumidity at around 60% to 70%. The gas mixtures were obtained with theaid of mass flow meters having an absolute precision of 0.2% of thedisplayed value (for example, displayed value 78%, precision=0.16% or78+/−0.16%); the oxygen concentration was checked with the aid of aspecific analyzer. At the end of the 3 hours of exposure, the rectalbody temperature of the rats was measured for each administrationtemperature.

Since rats are ordinarily used as a preclinical model for the study ofhuman physiology and pathologies, and given moreover that the normalbody temperatures Tc of rats and humans are of the same order ofmagnitude, the administration of a gas mixture at different temperaturesin rats in a closed enclosure is thus comparable to the administrationin humans of such a gas mixture at an inhalation temperature Ti which isroughly equal to the ambient temperature of the room in which the gastreatment is administered. The inhalation temperature Ti can be between16° C. and 27° C., for example.

For an inhalation temperature of 22° C., one determines:

points H22 and X22 located on the helium curve C1 and the xenon curveC2, respectively;

horizontal lines T32, T33, T34 and T35 corresponding to targettemperatures of 32° C., 33° C., 34° C. and 35° C.

In this way, for a distance H22-X22 representing the sum of thepercentages of helium and xenon in the inhalation gas mixture includingoxygen, xenon and helium, one gets:

a distance X22-T33 which represents the proportion of helium making itpossible to maintain the body temperature Tc at 33° C.,

a distance H22-T33 which represents the proportion of xenon making itpossible to maintain the body temperature at 33° C.,

a distance X22-T34 which represents the proportion of helium making itpossible to maintain the body temperature at 34° C.,

a distance H22-T34 which represents the proportion of xenon making itpossible to maintain the body temperature at 34° C.,

a distance X22-T35 which represents the proportion of helium making itpossible to maintain the body temperature at 35° C.,

a distance H22-T35 which represents the proportion of xenon making itpossible to maintain the body temperature at 35° C.

These experimental data thus made it possible to prepare table 2,presented in an appendix, which includes the proportions of a mixture ofhelium and xenon, while taking into account the proportion of oxygen. Itis clearly apparent that these proportions of helium and xenon dependboth on the temperature of the inhaled gas Ti, on the proportion ofoxygen present in the gas composition, and on the body temperature Tcthat one wishes to obtain. One then observes that the higher theinhalation temperature Ti, the higher the proportion of helium is formaintaining the body temperature Tc in a hypothermal temperature rangeset at below 36° C. and more specifically between 32° C. and 35° C.

More precisely, the distance H22-X22 corresponds to the differencebetween a body temperature of a rat inhaling an oxygen-helium mixtureand a body temperature of a rat inhaling an oxygen-xenon mixture, at thesame inhalation temperature of 22° C. The distance X22-T34 correspondsto the difference between a body temperature of rat inhaling anoxygen-xenon mixture at an inhalation temperature of 22° C. and a targetbody temperature of 34° C. In the same way, for an inhalationtemperature of 22° C., the distances X22-T32, X22-T33 and X22-T35correspond to the difference between the body temperature of the ratinhaling the oxygen-xenon mixture and the target body temperatures of32° C. to 35° C.

Taking into account the functions represented by the regression linesC1, C2, the proportions of the gas mixture to be complied with in orderto obtain a hypothermal mixture were determined according to thecalculation method described below.

Curve C1 represents the function y=0.526x+20.748 and curve 2 representsthe function y=0.3877x+30.075. For example, let us take the case inwhich one wishes to obtain a body temperature of 34° C. with an ambienttemperature of 22° C. and an oxygen level of 22%, that is to say a levelof inert gases of 78%:

A first step consists of a calculation of the body temperatures: for aninhalation temperature roughly equal to 22° C., when a 22% O₂-78% Hemixture is inhaled, one gets a body temperature of 32.32° C. using thefunction representative of curve Cl, and when a 22% O₂-78% Xe mixture isinhaled, one gets a body temperature of 38.60° C. using the functionrepresentative of curve C2.

From this one derives, in a second step, a difference, for theinhalation temperature of 22° C., between the body temperatures obtainedby the calculations in the first step, which will subsequently be usedas reference value for the calculations of the content of each of thecompounds of the mixture: a first difference D1 is thus calculatedbetween the body temperature obtained with a 22% O₂-78% Xe mixture andthe body temperature obtained with a 22% O₂-78% He mixture, and, in thecase described with an inhalation temperature equal to 22° C., a valueof 6.28 is obtained here.

A third step consists of a calculation of the content of one of thegases to be provided in order to ensure a body temperature of 34° C. foran inhalation temperature of 22° C. In the case described, onearbitrarily chooses to determine the helium content, it being understoodthat one could choose to first determine the xenon content. A seconddifference D2 is calculated between the body temperature obtained with a22% O₂-78% Xe mixture and the body temperature desired for thisinhalation temperature of 22° C., giving a value of 4.6 in this case.

This ratio between the values calculated in the second and third stepsis used in a cross product calculation in order to determine the heliumcontent, relative to the 78% of inert gases in addition to oxygen, ofthe gas composition to be prepared in order to obtain a body temperatureof 34° C.: In the case described, a content equal to 57% (4.6×78/6.28)%is obtained here. From this, the xenon content is derived by subtraction(78−57=21), and, in the present case, the composition then will consistof 57% helium, 22% oxygen, and 21% xenon.

According to this example and upon reading table 2, for an inhalationtemperature Ti of 22° C., an oxygen proportion of 22%, and a desiredbody temperature between 32° C. and 35° C., the composition includes 8to 33% xenon and 45 to 70% helium. More precisely, if one wishes toachieve a body temperature of 34° C., the composition includes 22%oxygen, 56% to 58% helium, and 20% to 22% xenon.

One also observes that, in all the cases, the composition includes atleast 9% helium and at most 65% xenon. More particularly, when theoxygen content is between 21 and 30%, the composition includes at least13% helium and at most 65% xenon. According to the present invention,the aim is a gas composition enabling, on the one hand, the presence ofthe target thermal properties, that is to say the thermal propertiesobtained with the aid of a hypothermal mixture of inert gases, it beingpossible to read in the tables the appropriate proportions for obtainingsuch a composition, and, according to the present invention, the aim isa composition enabling, on the other hand, a use on subjects withoutrisk of undesired anesthetic effect, that is to say by limiting theaddition of xenon to a maximum of 50%. In addition, for inhalationtemperatures Ti between 19° C. and 23° C., the composition includes 21to 30% oxygen, 26 to 77% helium, and 2 to 50% xenon. Preferably, forinhalation temperatures less than or equal to 22° C., the compositionincludes 22% oxygen, 45% to 47% helium, and 31% to 33% xenon.

In the same manner as described above, the graph of FIG. 2 representsthe experimental data Pi of the body temperature obtained in rats as afunction of the temperature of inhalation of helium (curve C1) or ofargon (curve C3), based on which the proportions of the different gasesin a helium-argon-oxygen mixture were calculated (table 3). As examples,the reference points A18 and H18 used in this case were taken at aninhalation temperature Ti of 18° C., and the distances with the targetbody temperatures T32, T33, T34 and T35 are thus representative of theproportions of the mixture of inert gases for this inhalationtemperature of 18° C.

A comparison between the graphs of FIGS. 1 and 2 shows that curve C3 hasa smaller slope than curve C2. In fact, curve C2 represents the functiony=0.3877x+30.075, whereas curve C3 represents the functiony=0.2328x+32.334, the argon having lower hyperthermal properties thanxenon. Thus, the proportions of the inert gases in the inhalation gascomposition according to the invention vary as a function of the qualityof the first compound used in this composition, which is selected fromargon or xenon.

Upon reading table 3, one observes that in all the cases the compositionincludes at most 67% argon and at least 8% helium. More particularly,when the oxygen content is between 21 and 30%, the composition includesat most 67% argon and at least 11% helium. In addition, for inhalationtemperatures Ti between 19° C. and 23° C., the composition includes 21to 30% oxygen, 20 to 76% helium, and 2 to 56% argon. And again forinhalation temperatures Ti of between 19° C. and 23° C., the compositionincludes 21 to 25% oxygen, 22% to 76% helium, and 2% to 56% argon.

Finally, these proportions make it possible to ensure that the mixtureof inert gases is hypothermal. When the gas composition is inhaled at agiven temperature Ti, it makes it possible to maintain the bodytemperature Tc of the subject inhaling it within a so-called hypothermalbody temperature range from 32° C. to 35° C., while avoiding a bodytemperature gradient between the skin and the internal organs.

In a non-limiting manner, the inhalation of such a composition can becarried out by means of a human-machine interface such as a respiratoryventilator, a face mask, respiratory goggles or any other type ofinterface.

Moreover, in order to avoid inhalation of just one or some of the inertgases, the packaging of such a composition is preferably carried out ina single container with the three compounds, namely xenon or argon,helium, and oxygen, in pre-established proportions under a pressurebetween 10 and 300 bar. The container has a volume of 0.1 L to 50 L.This packaging in a single bottle is referred to as “ready-to-use.” Inorder to ensure a proportion of at least 21% oxygen in the compositionand still obtain an inhalation gas composition, taking into account anuncertainty of 1% between the different steps existing between themanufacturing, the packaging and the administration of the gascomposition, and in order to avoid hypoxia for the subject to whom themixture is administered, the oxygen proportion in this type of packagingis always at least 22%.

APPENDIXES

TABLE 1 Chemical element Nitrogen (N) Xenon (Xe) Argon (Ar) Helium (He)Molecular 28.013 131.29 39.948 4.003 weight (mg/mol) Thermal 24.0015.107 16.483 146.20 conductivity (mW/m · K)

TABLE 2 % O2 = 21 % O2 = 22 TC = TC = TC = TC = TC = TC = TC = TC = 35°C. 34° C. 33° C. 32° C. 35° C. 34° C. 33° C. 32° C. T1 % He % Xe % He %Xe % He % Xe % He % Xe % He % Xe % He % Xe % He % Xe % He % Xe 16 14 6525 54

43 4

14 64 25 50 36 4

47 31 17 19 60 39 49 42 37

26 19 50 30 4

41

54 26 18 24 95 3

44 47 32 58 21 2

55 35

46

5

29 19

90 41 34

27 64 15 2

50 40 3

52 26 60 15 20 34 45 46 3

58 21 70  9 34 44 46 32 57 21

9 21 40 39 52 27 6

15 76  3 39 39 51 27 60 15 75 3 22 45 34 58 21 70 9 4

35 57 21 70 11 23 51 28 64 15 77 2 51 27 63 15 76  2 24 54 21 71  8 5721 70  8 25 64 15 78  1 6

15 77  1 26 71 8 70 8 27 76 1 77 1 % O2 = 23 % O2 = 24 TC = TC = TC = TC= TC = TC = TC = TC = 35° C. 34° C. 33° C. 32° C. 35° C. 34° C. 33° C.32° C. T1 % He % Xe % He % Xe % He % Xe % He % X

% He % Xe % He % Xe % He % Xe % He % Xe 16 14 60 25 92 35 42 46 31 14 6224 92 35 41 46 30 17 18 59 29 48 49

52 25 18

8 29 87 40 36

25 18 23 54 14 43 46 91 57 26 2

33

4 92 49

6 20 19 28 49 40 37 51 26 60 14 28 48

9 37 50 26 62 14 20

3 44 45

2 57 20 68 3 33 43 44 32 56 29 68 8 21

9 3

26 6

14 75 2 38

8 59 26 62 14 74 2 22 44

76 21 69  8 34 32 56 26 68  8 23

0 27 63 14 71  2 49 27 62 14 73  2 24

6 21 69 11 55 21 68 8 25 63 14 76  1 62 19 73 1 26 69  8 68  8 27 76  125  1 % O2 = 25 % O2 = 26 TC = TC = TC = TC = TC = TC = TC = TC = 35° C.34° C. 33° C. 32° C. 35° C. 34° C. 33° C. 32° C. T1 % He % Xe % He % Xe% He % Xe % He % Xe % He % Xe % He % Xe % He % Xe % He % Xe 16 1

62 24 51

40

30 13 61 24

34 40 45 29 17 18 37 29 46 39 36 50 25 18 54 28 46 39 35 49 25 18

32 30 32 45 31

30 22 52 31 41 34 30 53 19 19 27 48 39 36 30

61 14 27 47 38 36 49 25 60 14 20 32 43 44 31 35

67 8 32 42 43 31

4 20 69 8 21 38 37 49 26 61 14 76 2 37 37 49

60 11 72 2 22

32 53 29 62  8 42 32 34 20 66 8 23 49 26 61 14 73  2 48 26 60

72 2 24 55 20 67 8 54

66

25 61 34 78 1 60 14 73  1 26 67 8 67  7 27 74 1 73  1 % O2 = 27 % O2 =28 TC = TC = TC = TC = TC = TC = TC = TC = 35° C. 34° C. 33° C. 32° C.35° C. 34° C. 33° C. 32° C. T1 % He % Xe % He % Xe % He % Xe % He % Xe %He % Xe % He % Xe % He % Xe % He % Xe 16 13 60 23 56 34 39 44 29 13 5923 49

39 43 29 17 17 56 28 43 38 35 49 24 17 55 28 44 38 34 46 24 18 22 51 3340 43

0 54 19 22 54

2 46 4

29 53 19 19 27 46 37 36 48 25 59 14 26 46

35 48 24 58 14 20 11 42 43 36 54 19 65 8

41 4

30

19 64  8 21

36 48 25 59 14 71 2 36 36 4

25 38 14 76

22 42 31 53 20 65  8 41 31 53 19 64 8 23 47 26 59 14 71  2 47 25 58 1470 2 24 53 20 65

52 29 64 8 25 59 14 72  1 58 14 71 1 26 66 7 6

7 27 72 1 71 1 % O2 = 29 % O2 = 30 TC = TC = TC = TC = TC = TC = TC = TC= 35° C. 34° C. 33° C. 32° C. 35° C. 34° C. 33° C. 32° C. T1 % He % Xe %He % Xe % He % Xe % He %

% He % Xe % He % Xe % He % Xe % He % Xe 16 13 58 23 48

38 43

13 57 22 48 32 38 42 28 17 17 54 27 44 37 34 47

17 53 27 4

37 33 47 23 18 21 56 32 39 42 29 52 19 21 49 31 39 41 29 52 18 19 26 4536 35 47 24 5

13 26 44 36 34 46 24 57 11 20

40 41

2 19 60  8 30 4

41 29 32 18 62 8 21

35 4

24 38 13 69  2

35 46 24 37 13 6

2 22 41 36 52 19

8 40 30 51 19 62 8 23 4

25 58 13

2 45 25 57 13 68 2 24 52 19 64  7 51 19 63  7 25 58

70  1 57 10 69  1 26 64  7 63  7 27 70  1 69  1 % O2 = 35 % O2 = 40 TC =TC = TC = TC = TC = TC = TC = TC = 35° C. 34° C. 33° C. 32° C. 35° C.34° C. 33° C. 32° C. T1 % He % Xe % He % Xe % He % Xe % He % Xe % He %Xe % He % Xe % He % Xe % He % Xe 16 12 53 21 44 30 33 39 26 11 49 19 4128 32 36 24 17 10 49 25 46 34 31 43 22 14 46 23 37 32 28 40 20 18 29 4529 36 39 20 48 17 18 42 27 33 26 24 44 16 19 24 41 33

2 41 22 53 12 22 38 31 29 40 20 49 1

20 28 37 38 27 48 17

8 7 26 34 35 25 44 10 93

21 32 32 43 22 53 12 63 2 30 36 39 21 49 11 54

22 37 28 48 17 58 7

4 26 44 16 14 6 23 42 23 53 12 63 1 39 21 49 11

8 2 24 47 18 58  7 44 16 54 6 25 53 12 64  1 49 11 59 1 26 58 7 54 6 2764 1 59 1 % O2 = 45 % O2 = 50 TC = TC = TC = TC = TC = TC = TC = TC =35° C. 34° C. 33° C. 32° C. 35° C. 34° C. 33° C. 32° C. T1 % He % Xe %He % Xe % He % Xe % He % Xe % He % Xe % He % Xe % He % Xe % He % Xe 1610 43 18 17 23 30

3 27 9 41 16 34 23 27 30 20 17 13 42 21 34 29 26 17 18 12 38 19 31 26 2433 17 18 17 38 25 30

3 22 41 14 16 35 22 28 30 20 37 13 19 20 33 28 27 36 19 43 10 18 32 2624 33 17 41  9 20 24 31 32 23 40 15 49 6 22 28 29 21 37 13 44  6 21 2827 36 19 45 10 53 2 25 25 33 17 41 9 48  7 22 32 23 40 15 49 6 29 21 3713 45 5 23 36 19 45 10

4 1 32 18 41 9 49 1 24 40 1

49 6 36 14 43 5

25 45 10 34 1 41  9 49 1 26 49  6 45

27

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TABLE 3 % O2 = 21 % O2 = 22 TC = TC = TC = TC = TC = TC = TC = TC = 35°C. 34° C. 33° C. 32° C. 35° C. 34° C. 33° C. 32° C. T1 % He % Ar % He %Ar % He % Ar % He % Ar % He % Ar % He % Ar % He % Ar % He % Ar 16 12 6724 55 35 44 47 32 12 66 23 55 35 43 46 32 17 15 64 27 52 39 40 51 28 1563 27 51 40 39 51 27 18 19 66 32 47 44 35 57 22 19 50 31 47 44 34 56 2719 23 50 36 43 49 30 62 17 23 55 36 42 40 29 62 16 20 27 52 41 387 55 2469 16 27 51 41 37 54 24 68 10 21 32 47 47 32 61 18 76 3 32 48 46 32 6117 75 3 22 38 41 55 20 69 10 37 41 52 20 68 10 23 44 35 60 19 56 3 43 3559 19 76 2 24 51 28 68 11 50 28 67 11 25 59 26 77 2 58 20 76 2 26 58 1167 11 27 78 1 77 1 % O2 = 23 % O2 = 24 TC = TC = TC = TC = TC = TC = TC= TC = 35° C. 34° C. 33° C. 32° C. 35° C. 34° C. 33° C. 32° C. T1 % He %Ar % He % Ar % He % Ar % He % Ar % He % Ar % He % Ar % He % Ar % He % Ar16 12 65 23 54 34 43 45 32 12 64 23 53 34 42 45 31 17 15 62 27 50 38 3950 27 15 61 26 50 38 38 40 27 18 19 58 31 46 43 34 55 22 18 58 30 40 4234 55 21 19 22 55 35 42 48 29 61 16 22 54 35 41 47 29 60 16 20 27 50 4037 54 23 67 10 20 56 40 36 53 23 66 10 21 32 45 46 31 60 17 74 3 31 4545 31 59 12 73 3 22 37 40 52 20 67 10 30 46 51 25 66 10 23 43 34 59 1875 2 42 34 58 18 74 2 24 49 28 66 11 49 27 66 10 25 57 20 75 2 56 20 742 26 60 11 65 11 27 76 1 75 1 % O2 = 25 % O2 = 26 TC = TC = TC = TC = TC= TC = TC = TC = 35° C. 34° C. 33° C. 32° C. 35° C. 34° C. 33° C. 32° C.T1 % He % Ar % He % Ar % He % Ar % He % Ar % He % Ar % He % Ar % He % Ar% He % Ar 16 12 63 22 53 33 42 44 31 11 63 22 52 33 41 44 30 17 15 60 2640 37 38 49 26 14 60 26 48 37 37 48 26 18 18 57 30 45 42 33 54 21 18 5630 44 41 33 51 21 19 22 53 34 41 47 28 59 16 22 52 34 40 46 28 50 15 2026 49 39 36 52 23 65 10 20 48 39 35 52 22 65 9 21 31 44 45 30 58 17 72 330 44 44 36 58 16 71 3 22 36 30 50 25 65 10 35 30 50 24 64 10 23 42 3357 18 75 2 41 33 56 18 72 2 24 48 27 65 10 48 26 64 10 25 50 19 73 2 5519 72 2 26 64 11 63 11 27 74 1 73 1 % O2 = 27 % O2 = 28 TC = TC = TC =TC = TC = TC = TC = TC = 35° C. 34° C. 33° C. 32° C. 35° C. 34° C. 33°C. 32° C. T1 % He % Ar % He % Ar % He % Ar % He % Ar % He % Ar % He % Ar% He % Ar % He % Ar 16 11 62 22 51 32 41 43 30 11 61 21 51 32 40 42 3017 14 59 25 48 36 37 47 26 14 58 25 47 36 36 47 25 18 18 55 29 44 41 3252 21 17 55 29 43 40 32 52 20 19 21 52 33 40 46 27 58 15 21 51 33 39 4527 57 15 20 25 48 38 35 51 22 64 9 25 47 38 34 50 22 63 9 21 30 43 43 3057 18 70 3 29 43 43 29 56 16 66 3 22 35 38 49 24 63 10 34 38 48 24 62 1023 41 32 36 17 71 2 40 32 55 17 70 2 24 47 26 63 10 46 26 62 10 25 54 1971 2 53 19 70 2 26 62 11 62 10 27 77 1 71 1 % O2 = 29 % O2 = 30 TC = TC= TC = TC = TC = TC = TC = TC = 35° C. 34° C. 33° C. 32° C. 35° C. 34°C. 33° C. 32° C. T1 % He % Ar % He % Ar % He % Ar % He % Ar % He % Ar %He % Ar % He % Ar % He % Ar 16 11 66 21 50 31 40 42 2

11 59 21 49 31 39 41 29 17 14 57 25 46 35 36 46 23 14 56 24 46 35 35 4624 18 17 5 28 43 40 31 51 20 17 53 28 42 39 31 50 20 19 21 56 33 38 4427 56 13 20 50 32 38 44 26 55 15 20 25 46 37 34 50 21 62

24 46 37 33 49 21 61 9 21 29 42 42 29 55 16 67  1 29 41 42 28 54 18 62 322 34 37 48 23 62 9 33 17 47 23 61 9 23 39 32 54 17 69 2 39 21 53 17 682 24 46 25 61 16 45 25 60 16 25 53 18 69 2 52 18 68 2 26 61 16 60 10 2770 1 69 1 % O2 = 35 % O2 = 40 TC = TC = TC = TC = TC = TC = TC = TC =35° C. 34° C. 33° C. 32° C. 35° C. 34° C. 33° C. 32° C. T1 % He % Ar %He % Ar % He % Ar % He % Ar % He % Ar % He % Ar % He % Ar % He % Ar 1610 55 19 46 29 36 36 27 9 51 18 42 27 33 35 25 17 13 52 23 42 32 33 4223 12 48 21 39 30 30 30 21 18 16 49 26 39 36 29 47 18 14 46 24 36 54 2643 17 19 19 46 30 35 41 24 51 14 18 42 28 32 37 23 47 13 20 23 42 34 3145 20 57 8 21 39 31 29 42 18 52 8 21 27 38 39 20 51 14 63 2 25 35 36 2447 13 58 2 22 21 34 44 21 50 9 29 31 40 20 62 8 23 26 29 50 15 63 2 3827 46 14 58 2 24 42 23 56 9 39 21 32 8 25 48 17 63 2 44 10 39 1 26 56 951 9 27 64 1 59 1 % O2 = 45 % O2 = 50 TC = TC = TC = TC = TC = TC = TC =TC = 35° C. 34° C. 33° C. 32° C. 35° C. 34° C. 33° C. 32° C. T1 % He %Ar % He % Ar % He % Ar % He % Ar % He % Ar % He % Ar % He % Ar % He % Ar16 8 47 16 39 24 31 32 23 8 42 13 35 22 28 29 21 17 11 44 19 36 27 28 3619 16 40 17 33 25 25

18 13 42 22 33 31 24 39 16 12 38 26 36 28 22 36 14 19 16 39 25 36 34 2143 12 13 35 20 27 31 19 40 10 20 19 36 29 26 38 17 48 7 17 33 26 24 3515 44  6 21 23 32 33 22 43 12 53 2 20 30 30 20 39 11 48  2 22 26 29 3718 48 7 24 26 34 16 43 7 23 31 24 42 13 53 2 28 22 38 12 48 2 24 35 2047 8 32 18 43 7 25 41 14 54 1 37 13 49 1 26 47 8 43 7 27 54 1 49 1

indicates data missing or illegible when filed

1. An inhalation gas composition comprising oxygen and a mixture ofinert gases, characterized in that said mixture of inert gases includes:a first compound having hyperthermal properties, selected from xenon andargon, and a second compound having hypothermal properties, said mixtureof inert gases comprising proportions of the first compound and of thesecond compound such that the said mixture of inert gases ishypothermal.
 2. The gas composition according to claim 1, characterizedin that the second compound has organoprotective properties.
 3. The gascomposition according to claim 1, characterized in that the secondcompound is helium.
 4. The gas composition according to claim 1,characterized in that said composition includes at most 50% oxygen. 5.The gas composition according to claim 1, characterized in that saidcomposition includes 21 to 30% oxygen.
 6. The gas composition accordingto claim 1, characterized in that said composition includes 21 to 25%oxygen.
 7. The gas composition according to claim 1, characterized inthat said composition includes at most 50% xenon.
 8. The gas compositionaccording to claim 1, characterized in that said composition includes atleast 13% helium.
 9. The gas composition according to claim 1,characterized in that said composition includes 21% to 30% oxygen, 26%to 77% helium, and 2% to 50% xenon.
 10. The gas composition according toclaim 1, characterized in that said composition includes 21% to 25%oxygen, 43% to 48% helium, and 30% to 35% xenon.
 11. The gas compositionaccording to claim 1, characterized in that said composition includes22% oxygen, 45% to 47% helium, and 31% to 33% xenon.
 12. The gascomposition according to claim 1, characterized in that said compositionincludes roughly 22% oxygen, 43% helium, and 35% xenon.
 13. The gascomposition according to claim 1, characterized in that said compositionincludes 25% oxygen, 43% to 45% helium, and 30% to 32% xenon.
 14. Thegas composition according to claim 1, characterized in that saidcomposition includes at most 67% argon.
 15. The gas compositionaccording to claim 1, characterized in that said composition includes atleast 11% helium.
 16. The gas composition according to claim 1,characterized in that said composition includes 21% to 30% oxygen, 20%to 76% helium, and 2% to 56% argon.
 17. The gas composition according toclaim 1, characterized in that said composition includes 22% oxygen, 37%to 68% helium, and 10% to 41% argon.
 18. The gas composition accordingto claim 1, characterized in that said composition includes 25% oxygen,36% to 65% helium, and 10% to 39% argon.